Human papillomavirus (HPV): anogenital warts
Virus types
Human
papillomavirus (HPV) causes warts and anogenital malignancy. HPV can reside in
epithelial basal cellsand lead to subclinical or latent infection. Subclinical and
latent infection is probably responsible for most “recurrences” following
treatment of genital warts.
More than 30 HPV types are associated with genital warts. Patients are commonly infected with multiple HPV types. The HPV types producing genital infection are divided into two broad categories—those that produce benign lesions, or low risk types (HPV-6 and 11); and those associated with cancer, the so-called high-risk or oncogenic types (HPV-16 and 18).
Virtually all anogenital warts are
caused by “benign” HPV-6 and 11.
Epidemiology
Incidence
The
incidence of ano-genital warts is increasing rapidly and exceeds the incidence
of genital herpes. It is the most common viral sexually transmitted disease. It
is estimated that 30% to 50% of sexually active adults are infected with HPV
and only 1% to 2% of the aforementioned group has clinically apparent ano-genital
warts.
Age
The incidence is highest in young adults aged 16–24 years.
Sex
The
incidence and prevalence in males is higher than in females with a male: female
ratio of 1: 0.7
Predisposing
factors
Genital
warts have a high infectivity. The thinner mucosal surface is presumably more
susceptible to inoculation of virus than thicker keratinized skin, but in
addition lesions are commonest in sites subject to greatest coital friction in
both sexes. Subclinical infections are much more common than visible warts and
can be detected by the application of 5% acetic acid for 3-5 minutes that leads
to whitening of lesions (aceto-whitening).
Acquisition most commonly follows
sexual contact but ano‐genital warts are not always transmitted sexually. Perianal
warts may accompany genital warts, either due to local spread of infection or
to direct contact during anal coitus.
Approximately two‐thirds of sexual contacts of patients with genital warts
developed lesions within 24 months. The incubation period between contact and
diagnosis of genital warts is 3 weeks to 24 months, with a median of 3–10
months.
Regression and persistence
In most persons, genital HPV infection
appears to be transient, and tend to undergo spontaneous regression after about
1–2 years, whereupon HPV DNA becomes undetectable by PCR. Cell-mediated immunity
mediates the regression of HPV-induced lesions. Patients who are
immunocompromised because of a decrease in cell-mediated immunity are at
increased risk of developing and failing to eradicate HPV-related disease. This
includes organ transplant patients receiving immunosuppressive treatment and
patients with HIV infection.
Risk
The immune
status has an impact on the disease course and response to treatment. Cigarette
smoking is linked to the risk of anogenital warts in both men and women. This
increased risk of anogenital warts in smokers may reflect immune modulation
effects induced by cigarettes. The incidence of anogenital HPV infection is
increased 17-fold in renal transplant patients.
Genital HPV infection is strongly
associated with sexual intercourse. For women, insertive vaginal intercourse is
strongly associated with acquiring genital HPV infection. Condom use may be
partly, but not completely, protective for acquisition of genital HPV
infection. In men the risk of genital HPV infection is associated with being
uncircumcised, having had sex before age 17, having had more than six lifetime
sexual partners, and having had sex with professional sex workers. In men who have sex with men (MSM), anal HPV infection is
very prevalent (up to 75%).
Development of
intraepithelial neoplasia, cervical cancer, and other anogenital cancers
Approximately
15% to 28% of HPV DNA-positive women developed cervical squamous
intraepithelial neoplasia within 2 years. The risk of progression for HPV types
16 and 18 is greater (approximately 40%) than that for other HPV types. Male
circumcision is associated with a reduced risk of penile HPV infection.
Genital
warts in rare cases degenerate into squamous cell carcinoma (SCC). Nearly 30%
of vulvar carcinomas are associated with or preceded by condylomata. Men having
sex with men who have anal condylomata have a 50-fold relative risk for
developing anal cancer. HPV can lead to malignant anogenital lesions of the
cervix, vulva, anus, and penis.
Pathology
The most consistent histologic
features seen in condylomata include extreme
acanthosis and papillomatosis, parakeratosis, and koilocytosis. The
papillomatosis is more gently rounded than is seen in common warts. The upper
portions of the epithelia of mucosal surfaces normally have some degree of cytoplasmic
vacuolization, so the detection of koilocytesis specific for condylomata acuminata
only if present within the deeper portions of the spinous layer. The connective tissue is frequently very edematous and the
capillaries tortuous and increased.
Clinical
features
They are often asymptomatic, but may
cause discomfort, discharge or bleeding. They affect mucosal surface and
keratinized skin. The typical ano‐genital wart is soft, pink with numerous, discrete,
narrow-to-wide projections on a broad base. The surface is smooth or velvety
and moist, and lacks the hyperkeratosis of warts found elsewhere. Lesions are
frequently multifocal and have acuminate
topography, i.e. the tapering to a point. The
lesions are usually multiple especially on moist surfaces. The warts may coalesce
in the moist, occluded areas such as the perianal skin, vulva, and inguinal
folds to form a large, cauliflower-like mass. As a result of accumulation of
purulent material in the clefts, these may be malodorous. This classical ‘acuminate’ form constitutes about two‐thirds of ano‐genital
warts. Typical
sites of predilection are the area of the frenulum, corona and glans in men, and
the posterior fourchette in women; correspond to the
likely sites of greatest coital friction. Lesions may extend internally into
the vagina, urethra, or anal canal (but rarely beyond the dentate line), in
which case a speculum or sigmoidoscope is required for visualization and
treatment. Most other lesions are flat, though
more conspicuous than plane warts elsewhere, and some of these, generally on
non‐mucosal surfaces such as the penile shaft, pubic skin,
perianal skin and groins, may be sufficiently pigmented to resemble seborrheic keratoses. Both acuminate and flat types may coexist. Occasionally, only
lesions resembling common warts are seen, in men usually on the penile shaft,
and these may be the result of contact with common warts elsewhere on the
patient or on the sexual partner.
When perianal lesions occur, a prior
history of receptive anal intercourse will usually predict whether intra-anal
warts are present and will help to determine the need for anoscopy.
Warts spread
rapidly over moist areas and may therefore be symmetric on apposing surfaces of
the labia or anus.
Clinical variants
Oral
warts
Oral
warts
appear as small, soft, pink or white, slightly elevated papules and plaques on
the buccal, gingival or labial mucosa, the tongue or the hard palate. All
lesions are asymptomatic. Oral condylomata are associated with HPV types 6 and
11 and may result from digital or oral-genital sexual transmissions. In
HIV-positive patients, oral papillomas are frequently detected and may contain
unusual HPV types such as 7, 71, 72 and 73.
Complications
and co‐morbidities
Patients
with genital warts frequently have other sexually transmitted genital
infections. The presence of any type of ano‐genital
wart should raise the possibility that the patient may also be infected with
high‐risk HPVs and prompt screening for ano‐genital intraepithelial neoplasia.
Very
florid warts should warrant consideration of an underlying immune deficiency.
Disease
course and prognosis
The
duration of ano‐genital warts varies from a few weeks to many years.
Recurrences can be expected in about 25% of cases, because human papillomavirus
DNA can be demonstrated in clinically and histologically healthy normal skin
adjacent to lesions and this latent infection correlates well with recurrence
after clinical cure. The development of large masses, induration, pain, and
discharge raises the suspicion of malignant change and warrants immediate
biopsy.
Treatment
Because no effective virus-specific
agent exists for the treatment of genital warts, their recurrence is
frequent. As genital warts may cause
discomfort, genital pruritus, malodor, bleeding, and substantial emotional
distress, treatment is indicated if the patient desires it. Bleeding genital
warts may increase the sexual transmission of HIV.
HPV cannot
be completely eliminated because of the surrounding subclinical HPV infection.
Removal of visible lesions decreases viral transmission. All treatment methods
are associated with a high rate of recurrence that is likely related to
surrounding subclinical infection.
Management
of sexual partners
Examination
of sexual partners is not necessary for the management of genital warts because
the role of reinfection is probably minimal. Many sexual partners have visible
warts or probably already sub clinically infected with HPV. The use of condoms
may reduce transmission to a new uninfected partner. HPV infection may persist
throughout a patient’s lifetime in a dormant state and become infectious
intermittently. Whether patients with subclinical HPV infection are as
contagious as patients with exophytic warts is unknown.
Pregnancy
The use of
podophyllin and podofilox is contraindicated during pregnancy. Genital
papillary lesions have a tendency to proliferate and to become friable during
pregnancy. Many experts advocate the removal of visible warts during pregnancy.
HPV-6 and HPV-11 can cause laryngeal papillomatosis in infants. The route of
transmission is unknown, and laryngeal papillomatosis has occurred in infants
delivered by cesarean section. Cesarean delivery should not be performed solely
to prevent transmission of HPV infection to the newborn. In rare instances,
cesarean delivery may be indicated for women with genital warts if the pelvic
outlet is obstructed or if vaginal delivery would result in excessive bleeding.
Patient-applied therapies
Carefully
explain how to use the medication. Be sure that patients can identify the
lesions and understand the extent of the disease.
Imiquimod
Imiquimod is
available as a 5% cream. Clearance rates are 40% to 70% and there are lower
recurrence rates. Improved efficacy and lower recurrence rates occur with
imiquimod by inducing the body’s own immunologic defenses. Imiquimod has an
immunomodulatory effect and does not rely on physical destruction of the
lesion. It has antiviral properties by induction of cytokines. Imiquimod
enhances cell-mediated cytolytic activity against HPV. The cream is applied at
bedtime every other day and up to five times per week if tolerated, for a
maximum of 16 weeks. Patients use a finger to apply the medication into the
anal canal for anal warts. On the morning after application, the treated area
should be cleansed. Side effects are erythema, swelling, erosions, weeping,
crusting, scaling, itching, and burning. Imiquimod may induce local hyper- or
hypopigmentation. Wart clearance occurs by 8 to 10 weeks, or earlier. Systemic
reactions have not been reported. Imiquimod has not been studied for use during
pregnancy. Imiquimod cream is safe to use in organ transplant patients. It is
effective in HIV patients even with low CD4 counts.
Podophyllum resin
Podophyllin
is a plant compound that causes cells to arrest in mitosis, leading to tissue
necrosis. Podophyllum resin 10% to 25% in compound tincture of benzoin used to
be the standard provider-administered therapy.
Patient-applied medications are now commonly used. The medication can be
very effective, especially for moist warts with a large surface area and
lesions with many surface projections. Podophyllum is relatively ineffective in
dry areas, such as the scrotum, penile shaft, and labia majora. It is not
recommended for cervical, vaginal, or intraurethral warts. The compound is
applied with a cotton-tipped applicator. The entire surface of the wart is
covered with the solution, and the patient remains still until the solution
dries in approximately 2 minutes. When lesions covered by the prepuce are
treated, the applied solution must be allowed to dry for several minutes before
the prepuce is returned to its usual position. Powdering the warts after
treatment or applying petrolatum to the surrounding skin may help to avoid
contamination of normal skin with the irritating resin. The medicine is removed
by washing 1 hour later. The patient is treated again in 1 week. The
podophyllum may then remain on the wart for 8 to 12 hours if there was little
or no inflammation after the first treatment.
Over enthusiastic
initial treatment can result in intense inflammation and discomfort that lasts
for days. The procedure is simple and it is tempting to allow home treatment,
but in most cases this should be avoided. Very frequently patients over treat
and cause excessive inflammation by applying podophyllum on normal skin. To
avoid extreme discomfort, treat only part of a large warty mass in the perineal
and perianal area. Warts on the shaft of the penis do not respond as
successfully to podophyllum as do warts on the glans or under the foreskin;
consequently, electrosurgery or cryosurgery should be used if two or three
treatment sessions with podophyllum fail. Many warts disappear after a single
treatment. Alternate forms of therapy should be attempted if there is no
improvement after five treatment sessions.
Warning
Systemic
toxicity occurs from absorption of podophyllum. Paresthesia, polyneuritis,
paralytic ileus, leukopenia, thrombocytopenia, coma, and death have occurred
when large quantities of podophyllum were applied to wide areas or allowed to
remain in contact with the skin for an extended period. Only limited areas should
be treated during each session. Do not use podophyllum on pregnant women.
Provider-administered therapies
Cryosurgery
Liquid
nitrogen delivered with a probe, as a spray, or with cotton applicator is very
effective for treating smaller, flatter genital warts. It is too painful for
patients with extensive disease. Exophytic lesions are best treated with excision
or imiquimod. Warts on the shaft of the penis and vulva respond very well, with
little or no scarring. Cryosurgery of the rectal area is painful. A
conservative technique is best. Freeze the lesion until the white border
extends approximately 1 mm beyond the wart. Overaggressive therapy causes pain,
massive swelling, and scarring.
A blister
appears and erodes to form an ulcer in 1 to 3 days, and the lesion heals in 1
to 2 weeks. Repeat treatment every 2 to 4 weeks as necessary. Two to three
sessions may be required.
Use EMLA
cream and/or 1% lidocaine injection for patients who do not tolerate the pain
of cryotherapy.
Cryotherapy
is effective and safe for both mother and fetus when applied in the second and
third trimesters of pregnancy.
Surgical removal and
electrosurgery
Excision
with scissors, curettage, or electrosurgery produces immediate results. These
methods are useful for both extensive condylomata and a limited number of
warts. Small isolated warts on the shaft of the penis are best treated with
conservative electrosurgery or scissor excision rather than subjecting the patient
to repeated sessions with podophyllum. Large, unresponsive masses of warts
around the anus or vulva may be treated by scissor excision of the bulk of the
mass, followed by electrocautery of the remaining tissue down to the skin
surface. Removal of a very large mass of warts is a painful procedure and is
best performed with the patient receiving a general or spinal anesthetic in the
operating room.
Trichloroacetic acid
Application
of trichloroacetic acid (TCA) 50% to 90% is effective and less destructive than
laser surgery, electrocauterization, or liquid nitrogen application. It is most
effective on small, moist warts.
This is an
ideal treatment for isolated lesions in pregnant women. A very small amount is
applied to the wart, which whitens immediately. The acid is then neutralized
with water or bicarbonate of soda. The tissue slough heals in 7 to 10 days.
Repeat each week or every other week as needed. Excessive application causes
scars. Take great care not to treat normal surrounding skin.
Carbon dioxide laser
The CO2
laser is an ideal method for treating both primary and recurrent condylomata acuminata
in men and women because of its precision and the wound’s rapid healing without
scarring. The laser can be used with an operating microscope to find and
destroy the smallest warts. For pregnant women, this is the treatment of choice
for large or extensive lesions and for cases that do not respond to repeated
applications of trichloroacetic acid.
Prevention
The
introduction of the anti‐HPV vaccine is likely to result in a reduction of incidence
of ano‐genital warts.
The three HPV vaccines that have been introduced
worldwide over the past decade are aimed at achieving universal vaccination of
children and adolescents, ideally before 12 years of age. This would be prior
to the onset of sexual activity and when the strongest immune response is
generated, with CDC recommending “catch-up” shots for those ages 13–26 years.
Gardasil® (a quadrivalent vaccine against HPV 6, 11, 16 and
18) and Gardasil®9 (a 9-valent vaccine that
contains VLPs for HPV-6 and -11 as well as high-risk HPV types 16, 18, 31, 33,
45, 52, and 58) are approved for use in female and male individuals 9 to 26
years of age to prevent anogenital warts as well as genital and anal dysplasias
and cancer. Cervarix™, a bivalent vaccine against HPV 16 and 18 is FDA-approved
for use in girls and women ages 9 to 26 years to prevent genital dysplasia and
cancer. Vaccination consists of three IM injections probably within a period of
6 months according to the following schedule: 0, 2, and 6 months for Gardasil
and 0, 1, and 6 months for Cervarix.
Obviously, these vaccines are most effective when all doses are
administered before onset of sexual contacts.
